Investigates microglial repopulation mechanisms after csf1r inhibition, suggesting new therapeutic avenues.
Background Microglial repopulation after depletion via colony-stimulating factor 1 receptor (CSF1R) inhibition holds therapeutic potential for neurological disorders, but the cellular sources remain debated. We investigated whether repopulation arises solely from surviving microglia or also from nonmicroglial progenitors. Methods Using Cx3cr1 CreER :Ai14 (tdTomato) reporter mice, we labeled microglia before PLX3397-induced depletion and assessed repopulation. Next, in Cx3cr1 CreER+/− :Csf1r fl/fl mice, we combined tamoxifen-induced genetic CSF1R deletion with PLX3397 to ablate microglia completely and evaluated recovery. Results We found that repopulated microglia were predominantly tdTomato + , indicating derivation from surviving Cx3cr1 + microglia. Combined tamoxifen and PLX3397 achieved near-complete ablation, yet microglia repopulated and were re-depletable by PLX3397, confirming potential nonmicroglial origins. Conclusion Microglial repopulation primarily involves proliferation of surviving microglia but can recruit nonmicroglial progenitors when depletion is exhaustive. These insights resolve prior inconsistencies and guide therapeutic strategies for microglial replacement treatment.
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Wang et al. (2026) studied this question.
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